2 (meta-aminobenzenesulfonamido) 5-halopyrimidines and method of preparing same



Patented May 2, 1950 2 (META AMI-NOBENZEN E SUDFONAIWIDO )'5- HALO'PYR IlyIIIlINES AND METHOD OF PRE- PARING SAME Jackson PQEngli'sh, Stamford, and 'Joe' H.- Clark, Greenwich, Conn assignor's to American cyanam'id Company, New York, N; Y., a' corporation of Maine No Drawing. Application February 14, 1945, Serial N0. 577,946

7 Claims. 1 This invention relates to new organic cornpounds, which have been found to have surprising therapeutic effects, and to methods of preparing these new products.

During the past few yea-rs many para-aminobenzene sulfonami'des' have been prepared arid described. Some of these sulfanilainides, notably sulfadiazine, sulfaguanidine, sulfathiazole, and others, have been found to possess marked fbac'terio'static and bacteriocidal properties. Although a few meta-aniinobenzene sulfor'ialmides have been prepared, tested-, and found to possess slight therapeutic activity, it is generally agreed that those known sulfonamides which have an amino groupin the meta position on the benzene ring have little, if any, activity against bacteria, and are of little value in the treatment of infectious diseases.

Although several known sulfanilamides are highly efiicacious against gram-positive bacteria, they appear to be of no significant value in the treatment of malaria, sleeping sickness, filariasis, and other diseases caused by an infestation of the blood stream by protozoa. This applies with respect to both paraand meta-aminobenzene sulfonamides of previously known constitution. Some control of malaria, a disease caused by protozoans of the genus Plashiodium, has been" attained by the use of quinine or complex sutstances of synthetic origin, but these drugs are difi'icult to obtain or manufacture, are expensive, and are not as efiective as could be desired. Also, there is no known drug which is prophylactic with respect to malaria .organisms-.-

Despite the previously known therapeutic behavior of sulfonamicles we have discovered that certain meta-aminobenzenesulafonamidodiazines can be prepared and these compounds are surprisingly effective, both as prophylactic and ourative agents, against protozoal organisms of the type which cause avian malaria.

The compounds of the. present invention which possess these unusual properties may be represented by the formula in which X represents hydrogen, a cationic saltforming radical. or an alkyl radical, and. Dz represents a; diaz'ine radical, substituted or unsubstituted.

The nitrogenv atom of the free meta-amino radical may be substituted v'rith substituents other than hydrogen. since it has been found that such derivatives can be converted in the. body into those having a free amino group. These derivatives, also being new and useful compounds, are included within the scope of the present inven-'- tion. Among such derivatives are those meta substituted-benzenesulfonamidodiazines in which the meta substituent is a nitro, azo, azido, imido radical or a substituted amino radical such as acylainin'o, alkylar'nino, arylamino, a'zoinethine', including mono-aldoseamino; ureiclo, or the like.

As will be seen, the meta 'substituent' iii-the above formula may be represented bythe symbol 3 which includes the radical -NHz and any radical convertible into an amino radical such as NO2, -N=N,

ndnehydroxylated, inert solvent such as benzene,

ether, chloroform, dioz'iane, or the like. The reaction may be caused to take place at any temperature' fromab'out 0 C. to .C., or higher. The time required to bring about cdupimg or the sul'fonyl halide and the amino diazine. will depend upon the temperature or the reaction, and may be from aboutfifteeri minutes tosevarty-two: hours, the mwer temperatures requ rmg; of course, longer reaction times. The" mere- 3 nitro group of the resulting product is then reduced by methods known to those skilled in the art to obtain the desired meta-aminobenzenesulfonamidodiazine.

The necessity of reducing the nitro group may be avoided by starting with meta-aminobenzenesulfonyl fluoride and reacting this compound with any desired aminodiazine. This reaction gives the ineta-aminobenzenesulfonamidodiazine directly.

Another analogous method involves the reaction of a meta-acylaminobenzenesulfonyl halide with a desired aminodiazine. The acylamino group of the resulting product is then hydrolyzed to an amino group. These reactions are illus trated in Examples 36 and 37. Y

Another distinct method of preparing the compounds of the present invention comprises reacting a meta-aminobenzenesulfonamide with any 2-halodiazine. This reaction is carried out in the presence of a, moderately strong, inorganic base, such as potassium carbonate, sodium carbonate or calcium carbonate or other inorganic, alkaline substance free from hydroxyl groups with the reactants dissolved in a high-boiling, non-reactive solvent such as nitro-benzene, kerosene, polychlorobenzene, or the like, at 160-180 C. This is also illustrated in the specific examples; for instance, Example 26. Of course, meta-nitroor meta-acylaminobenzenesulfonamides may be used instead of the meta-amino compound but the resulting product must'be reduced or hydrolyzed, as the case may be, to obtain the desired meta-amino compound.

A still further method of preparing the compounds of the present invention comprises the steps of reacting a meta-nitrosulphenyl halide with an aminodiazine at relatively low temperatures (535 (3.), followed by oxidation of the sulfur group with, for example, potassium permanganate at room temperature or chromic acid anhydride in glacial acetic acid at temperatures around 90 C. The resulting meta-nitrosulfonamide is then treated with reducing agents to reduce the meta-nitro group to a meta-amino radical.

As will be apparent from what has been said and from the specific examples which follow, many different types and kinds of metanilyldiazines may be prepared. The diazine group may be that of a pyrimidine, pyridazine, or pyrazine. The diazine ring may be free from substituents, other than those forming the sulfonamido group, or it may be substituted at any one or more of the remaining three possible places with one or more alkyl, alkoxy, alkoxyalkyl, carbalkoxy, .carboxy, alkaryl, aryl, amino, nitro, halogen, or like radicals. In some cases, as when using 2- aminoquinoxaline (Example 34) as the diazine intermediate, the substituents may form a closed ring on the diazine nucleus. Some of these substituents may be added to the diazine ring after formation of the sulfonamidodiazine as in Example 43. This is particularly advantageous where the substituent would interfere with the coupling of the intermediates. Similarly, a benzenesulfonyl halide may be coupled with a suitable diazine and the product nitrated to yield metanitrobenzenesulfonamidodiazine after which the nitro group may be reduced to an amino group. This procedure is shown in Example 44.

A still further modification comprises the steps of preparing metanilylguanidine and converting this compound to 2-metanilamido-4,6-dimethylpyrimidine by heating with acetylacetone. Other compounds may be prepared by reacting metanilylguanidine with other 1,3-diketones, diesters, or keto-esters.

As the hydrogen of the sulfonamido group is acidic in character, it may be replaced with cationic salt-forming radicals by direct reaction with alkali-metal hydroxides or alkoxides. These salts may be recovered and used as such if desired. Salts of heavy metals such as copper, iron, aluminum, arsenic, chromium and the like may be obtained by reacting an aqueous solution of an alkali metal salt with a solution of the desired heavy metal salt. Salts of strong, high boiling amines, such as morpholine, phenylpropylamine and the like may also be prepared. The acidic hydrogen may also be replaced by alkyl radicals such as methyl, ethyl, propyl, or the like, by reaction with a diazoalkane, such as diazomethane, diazopropane, or the like, as illustrated in Example 4.5.

The invention will now be described in greater detail by means of the following specific examples which set forth the preparation of representative compounds of the present invention by several of the different methods discussed above. It will be understood, of course, that these examples are intended to illustrate specific aspects of the invention and are not intended to limit it to the particular reactants or reaction conditions described. All parts are by weight unless otherwise indicated.

EXAMPLE 1 2- (mmitrobenzenesuljonamido) pyrimidine 22 parts of m-nitrobenzenesulfonyl chloride and 14 parts of 2-aminopyrimidine were mixed with 25 parts of anhydrous pyridine and the reaction mixture was heated for 10 minutes on the steam bath, and after 30 minutes standing was poured into 700 parts of water. The 2-(m-nitrobenzenesulfonamido) pyrimidine was filtered ed and dried. The product may be purified by solution in alkali, treatment with charcoal, filtration, and reprecipitation with acid. 19 parts melting at 217-219 C. were obtained.

EXAMPLE 2 Z-metanilamidopyrimidine 2- (N -acetylmetanilamido) pyrimidine 0 CHJ JNH w r mixed w 9' o-9 r i1dineand t e.

.rwmternpera 1 .wasthje pnured-iiito Flo- 'A'ssuspensioniof parts of. 2+;netanilarnidopyrimidineas prepared in Example z-xwas suspended in .15 parts ofacetic .anhydride-zandreflugged for 45 minutes. Themixturezwas cooled'and the-solid was filtered. .aThez2e-(NLacetYImetanilamido) pyrimidine was-purified :hy"extrac1 i0n with h d ochloricacid followed by solution in ammonia and repre cipitation with: acid. :It melted at24 2-243-" C. iblo'ck) EXAMPLE *4 2- menitrobeneenesuljonamidol-+:5.+chlopyrim- "mine 522 parts :-.of .:mrnitrohenzenesulfonyl chloride and-il2zpartsioffieamino -chloropyrimidine (prepared by the chlorination of: aminopyrimidine in acidrsolution') were mixedwit-h 70 parts of --pyri dinerand refiuxedr-for two.hours. This solution wasponredinto1400 partsyof water containing 75 parts of hydrochloric acid. "The separated solid was :iiltered, ":The 2-.(m.-nitrobenzenesulfonamido) e5.-.:chloropyrim idine was. purified by solution; in alkali, filtratiomand reprecipitation with acid after treatment with charcoal. The product melted at 234-23'7..C.

.5 2-metaniZamido-5-chloropyrimidine HzN 'N OSOaNH A s s on of lilra s t e nit o ompound prepare in Ex mp e A wa sus en in 0 pa t oil 1 ammonium hydroxide. The suspension was saturated with hydrogen sulfide and boiled until a .solidseparated. The mixture was cooled, acidified with acetic acid,.a nd filtered. Theg metanilamidO.,.5.-.chloropyrimidine ,was purified by .solution in alkali, filtration, and precipitation with acid after treatment with charcoal. 12 parts, me tinsat 2.28 e e bta ne EXAMPLE .16

2- (N -acetylmetanilamz'do) -5chlor.opyrimidine d aa :P epare n EX n-re e were sue '1 a tsa c a h dride an r fl xed fo on ho Th o d u p e cnw 'fi erse an ashed- -T- l1e. x2 c t lmeta i emisiw 5 chloropyrimidine was ,pur-ified Joyex-traetion with acid followed by solution in. all;a1-i andreprecipitation after filtration. The melting point of the product was 256-258 C.

7 EXAMPLE 7 V V 2- (m-nitrobenzeneswlfonamido) -4-methyl;oy- -rimzdine- O CHa /NE .10 parts of in-n trobenzenesulionyl chloride and 22 parts of 2 -amino+1onethylpyril n' inc @6- tion i u e was all wed i stan f or l1 h 1 .1 a

parts of water containing 15.9 parts of hydrochloric. acid and the re i t ted nitro c m was filtered. The "2-(m nitrobenzenesulfonamido) -4-methylpyrimidine was purified by solution in alkali and treatment with charcoal. The melting point was227-229 C.

EXAMPLE :8

.3 metanilamigio4=methylpyrimidine 3 I I A v A rnixturecf l6 parts of the nitro compound preparedin Example --7 and 100 parts of 1:1- ammonia was saturated with hydrogen sulfide with cooling. The orangesol-ution Was then boiled until it solid-s p ated- :A te c o in t i wa fied with acetic acid-and filtered. The collected 2-metanil-amido-4-methylpyrirnidine was purified by solution in alka-li, filtration, and reprecipitation with acid after treatment with charcoal. Further purification was effected by treatment charcoal in acid solution. lhemeltingpoint was:210.-.i21310.

EXAMPLE 9 ..2:.(menitrobenaenesuljonamido) -4 ,6-dimethylpyrimidz'ne 22 parts of m-nitrobenzenesulfonyl chloride and 20 parts of 2 amino 4,-5-dimethylpyrimidine were mixed with parts of pyridine and kept at room temperature for 18 hours. The thick solution was poured into .500 parts 'of'water containing parts of hydrochloric acid. The precipitated 2-(m-nitrobenzenesulfonamido) 4,6 dimethylpyrimidine :was "collected and purified by treatment '--with charcoal in alkaline solution.

. EXAMPLE 10 Zemetanilamidoe4,6 dimcthylpyrimidme 'HQN CH3 50 parts of the nitrpcompcund prepared in Example 9 were suspended in 250 parts of 1:1 ammonia-"and-thissuspension was saturated with hydrogen sulfide. The resulting solution was boiled until a solid .had separated and then cooled and acidified. .'I;he 2-metanilamidoAKi-dimethylpyrimidine was collected and purified'by treatment w th .qh pa in alka ne-solut onsolution followed by precipitation with acid.

EXANIPLE 12 2-metanilamido-4-ethoxypyrimidine HaN N C 3 50 parts of the nitro compound from Example 11 were suspended in 250 parts of 1:1 ammonia and the mixture was saturated with hydrogen sulfide in the cold. The resulting solution was boiled until a solid separated and it was then cooled and acidified. The precipitated 2-metanilamido-4-ethoxypyrimidine was collected and purified by treatment with charcoal in alkaline solution.

EXAMPLE 13 2- (m-nitrobenzenesulfonamido) -4-aminopyrimidine 22 parts of m-nitrobenzenesulfonyl chloride and 18 parts of 2,4-diaminopyrimidine were mixed with 50 parts of pyridine and warmed at 50 C. for four hours. The resulting mixture was poured into 500 parts of water containing 75 parts of hydrochloric acid. The precipitate was collected and the 2-(m-nitrobenzenesulfonamido)- 4-aminopyrimidine was purified by solution in alkali filtration, treatment with charcoal, and precipitation with acid.

EXAMPLE 14 Z-metanilamido-4-aminopyrimidine HzN NH: i

50 parts of the nitro compound prepared in Example 13 were suspended in 200 parts of 1:1 ammonium hydroxide and the mixture was saturated with hydrogen sulfide. The resulting solution was boiled until a solid separated and was then cooled and acidified. The precipitated 2- metanilamido-l-aminopyrimidine was collected and purified by solution in alkali, filtration, and treatment of the filtrate with charcoal.

EXAMPLE 15 2- (m-nitrobenzenesulfonamido) -4-amino-5- bromopyrimidine OQN NH:

22 parts of m-nitrobenzenesulfonyl chloride and 30 parts of 2,4-diamino--bromopyrimidine (prepared by the bromination of 2,4-diaminopyrimidine in acid solution) were mixed with 75 parts of pyridine, and the mixture was heated on the steam bath for one hour. The resulting solution was poured into 500 parts of water containing 75 parts of hydrochloric acid, and the precipitate was filtered. The 2-(m-nitrobenzenesulfonamido) 4 -amino-5-bromopyrimidine was purified by solution in alkali, filtration, and treatment with charcoal followed by precipitation with acid.

EXAMPLE 16 2-metanilamid0-4-amin0-5-bromopyrimidine 50 parts of the nitro compound prepared in Example 15 were suspended in 200 parts of 1:1 ammonia and the mixture was saturated with hydrogen sulfide. The resulting solution was boiled until a precipitate formed and was then cooled and acidified. The precipitated Z-metanilamido-4-amino-5-bromopyrimidine was collected and purified by treatment in alkaline solution with charcoal, followed by precipitation with acid.

EXAMPLE 17 EXAMPLE 18 2-metanilamido-4-phenylpyrimidine C aHfi 50 parts of the nitro compound prepared in Example 17 were suspended in 250 parts of 1:1 ammonia and the suspension was saturated with hydrogen sulfide. The resulting solution was boiled until a solid separated and was then cooled and acidified. The precipitated Z-metanilamido- 4-phenylpyrimidine was collected and purified by treatment in alkaline solution with charcoal.

EXAMPLE 19 2(m-nitr0benzenesulfonamido) -5-carbethomypyrimidine OZN N SOaNH 0 0201115 22 parts of m-mtrobenzene'sulfonyl chloride and 25 parts of 2-amino-5-carbethoxypyrimidine (prepared by the reaction of guanidine with carbethoxymalondialdehydeacetal) were mixed with 50 parts of pyridine and heated at C. for two hours. The resulting solution was poured into 500 parts of water containing '75 parts of hydrochloric acid and the precipitated 2-(m-nitr0benzenesulfonamido) 5 -carbethoxypyrimidine was collected and purified by treatment in cold alkaline solution with charcoal.

EXAMPLE 20 2-metanilamido-5-cwrbethomypyrimidine To a slurry prepared by heating 60 parts of iron powder with 200 parts of 5% acetic acid was added with stirring 50 parts of the nitro compound prepared in Example 17. The mixture was heated and stirred on the steam bath until it became completely black after passing through an intermediate yellow stage. The slurry was cooled and made alkaline with sodium carb Themixture was filtered and Z-fme'thaniIamidof -"carbethoxypyrimidine was precipitated from the filtrate, after treatment with charcoal, by acidification. Further purification was obtained by redissolving in cold alkali and treatment of this solution with charcoal, followed by precipitation with and; t

In this examplereductiofi of the meta nitro i group was accomplished byv means of hydrogen formed as the result of the action of an acid on a metal.

EXAMPLE 21 z-memnizamido-searzwaeylizifimidm 50 parts of 2#netanilamido+5. carbethoxypyrimidine, as prepared'in Exarnplejl8,'wasdissolved m 200 parts of water containing parts of sodium hydroxide and the resulting solution was refluxed for one hour 2ernetanilamido-5-carboxypyrimidine was precipitated at the end of this time by acidification. Further purification was obtained by treatment of its alkaline solution with charcoal.

EXAMPLE 22 4- (m-nitfohefizeviesulfonamido) pyrimidine N02: r. r I

22 parts of m-nitrobenz'ene'sulfonyl chloride and 14' parts of 4-aminopyrimidine were mixed with parts of pyridine and'fthe' mixture was allowed to stand for 1-8 hours. After this time it was poured into 500 parts of water containing I 75 parts of concentrated hydrochloric acid. The precipitated 4-(m-nitrobenzenesuliona nidolpyrimidine was collected and purified by solution in alkali, filtration, treatment of the alkaline filtrate with charcoal, and precipitation with acid. It will be noted that in'this 'example4-aminopyrimidine is used in place of the 2-aminopyrimidine of the previous examples.

4 -metanilamidopyrimidine 59 parts of 4- m-nitrobenzenesulfonamidol pyrimidine, as preparedin Example 22, were suspended in 200 parts of l 1 ammonia and the mix} ture' was saturated with hydrogen sulfide with cooling. The resulting solution-wasfboileduntil a solid formed and was thencooled and acidified. t

The precipitated 4-metanilainiidopyrimidine was purified by solution in alkali filtration, and treatment of the alkaline filtrate with charcoal, followed by precipitation'with acid:

EXAMPLE 24 a 5- (m-nitrobenzenesulfonamido) pyrimidine 22 parts of m-nitrobenz eneslflfonyl chloride and 14 parts of 5-aminopyrimidine were' inixed with 50 ccfof pyridine, and the" mixture was heated on the steam bath for J inmutea The resulting sunfish was then poured into 500 parts conta in; 75 parts; of hydrochloric acid. 'pitated 5-( n nitrobenzenesulforiamiine' was; collected and purified by solutio'ri in alk' renewe by treatment of its alkal nfe' solution withcharcoal, The diazine used in this example was 5-'aniinopyrimidine.

EXAMPLE 25 5wtiihiiafiiiddiiyrimidme N H5 I parts of 5-(m-nitrobenzenesulionamido)pyrimidine from Example 24 was suspended in 200 parts of 1:1 ammonia and the suspension was saturated with hydrogen sulfide. The resulting solution was" boiled until a'sond precipitated and was then coole'd and acidified. The precipitated 5metanilainid0pyrimidine was purified 'by solution in alkali-g filtration, treatment of the alkaline filtrate with charcoal, and precipitation with acid;

EXAMPLE 26 z-memnizamidopymihe H2N N SO2NH N 41 ait'sbf eniropyrazifie, 62 parts of metanilamide and parts of anhydrous potassium carbonate were heated at 160-180 C. for five hours with stirrin''and, refluxing. The mixture was thencooled and dissolved in about parts of water; This solution'was steam distilled to remove th unreacted chloropyrazinel Unreacted I'nejtanila'm'ide was precipitated by adjustment of thepi-Ito f7.5 -8 and it was filtered. The filtrate was acidified with an excess of acetic acid to precipitate the 2 -metanilamidopyra zine. This ctedjandfurther purified by treatment in ac d and alkaline solution with charcoal. The m l tl'll'g pbiht Wa 22 8' 230 C. ChIOlOpyI'aZihe was used as the diazine in this example. Preparation of this compound i's'dscribed in the copendingapplication of .Philip S. Winnek, Serial No. 499,993, filed August 25, 1943, now Patent No. 2,396,066. Itwill also be noted that chloropyrazine is reacted directly with metanilamide, thus avoiding the use of a sulfonyl chloride.

I EXAMPLE 27' a demarch iiefiesuifomzmido) pyridazme EXAMPLE 28 S-metam'ldmidopyrz'dazine HzN v OSes-aw 50 parts of 3-(m-nitrobenzenesulfonamido) pyridazine, as prepared in Example 27, were suspended in 200 parts of 1:1 ammonia and the suspension was saturated with hydrogen sulfide. The resulting solution was boiled until a solid precipitated and was then cooled and acidified. The separated 3-metanilamidopyridazine was purified by solution in alkali, filtration, and treatment of the alkaline filtrate with charcoal.

EXAIVIPLE 29 (3-uitrobeuzenesuljonamido) Z-chloropyrimidine 33 parts of 5-amino-2-chloropyrimidine were dissolved in 100 parts of anhydrous pyridine at 50-60 C. 62 parts of m-nitrobenzenesulfonyl chloride were added to the solution at about 60 C. When the mixture had reached room temperature it was poured into 1000 parts of water and the mixture was neutralized. The 5-(3- nitrobenzenesulfonamido) 2 chloropyrimidine was collected and purified by treatment in alkaline solution with charcoal.

EXAMPLE 30 5-metanilamido-2-chloropyrimidine 150 parts of iron dust were slurried with 300 .parts of 2%% acetic acid. When the foaming had stopped 47.5 parts of 2-chloro-5-(3-nitrobenzenesulfonamido)pyrimidine were stirred in and the mixture was heated with stirring for one hour. It was then cooled, made basic, and filtered. The filtrate was clarified with charcoal and the 5-metanilamido-2-chloropyrimidine was precipitated by acidification with acetic acid.

EXAMPLE 31 Sodium salt of Z-metanilamidopyrimidine EXAlVl'PLE 32 Purification of 2-metaniZamid0-5- chloropyrimidine 2-metanilamido-5-chloropyrimidine may be purified advantageously by preparing and recrystallizing the hydrochloride.

5 parts of 2-metani1amido-5-chloropyrimidine are dissolved in '70 parts of boiling water con- 12 taining 3 parts of concentrated hydrochloric acid. The hot solution is treated with charcoal, filtered, and cooled. The precipitated hydrochloride is collected and transformed into the free compound with ammonia or sodium acetate.

EXAIVLPLE 33 Sodium salt of 2-metam'Zamido-5- chloropyrimidiue HaN N 3 01 114 parts of 2-metanilamido-5-chloropyrimidine were dissolved in parts of water and 41 parts of 10 N sodium hydroxide. The solution was diluted with 25 parts of absolute alcohol, treated with charcoal, and filtered. 950 parts of alcohol were added to the filtrate and the solution was chilled to precipitate the sodium salt. The precipitated hemihydrate of the sodium salt of 2-metanilamido-5-chloropyrimidine was collected and dried.

EXAMPLE 34 2- (3-nitrobenzenesulfonumido) quinowaline OQN OSOME 10 parts of 2-aminoquinoxa1ine (J.A.C.S. 66, 1958 (1944)) were suspended in 80 parts of anhydrous pyridine and to thiswas added 25 parts of m-nitrobenzenesulfonyl chloride. The whole was allowed to stand for 24 hours and then poured into 200 parts of water. The Z-(S-nitrobenzenesulfonamido)quinoxaline was filtered off and purified by dissolution in alkali, treatment with charcoal, and reprecipitation with acid. The substituted diazine, 2-aminoquinoxaline, is used as the intermediate in this example.

EXAMPLE 35 2-metauilamidoquiuomaline v uin 40 parts of 2 (3 nitrobenzenesulfonamido quinoxaline were dissolved in 250 parts of 1:1 aqueous ammonia. The mixture was saturated in the cold with hydrogen sulfide and concentrated to half volume over. an open flame. The mixture was acidified and the solid filtered. The 2- metanilamidoquinoxaline was extracted with alkali and precipitated from the alkaline solution with acetic acid.

EXAMPLE 3s 2- (M-dcetylmetanilamido) pyrimidine O CHs lNH 16 parts of 2-aminopyrimidine were suspended in 42 parts of anhydrous pyridine. 42 parts of acetylmetanilyl chloride were added with stirring in one hour at 40-60 C. After the mixture had cooled somewhat it was poured into an equal areas-st 13 volume of water and the precipitated 2-(N -acetylmetanilamido)pyrimidine was filtered off. It could be purified by solution in alkali and reprecipitation.

EXAMPLE 37 2-metanilamid0l yrimidine EXAMPLE 38' 2- (3-nitrobenzenesulfonamido) pyrimidine To 50 parts of 2-aminopyrimidine,dissolved in one liter of dry benzene, was added a solution of 50 parts of m-nitrobenzenesulfenyl chloride (Chem. Zentr. 34, II, 763) in one literof dry benzene. The precipitate was filtered and the desired 2-(m nitrobenzenesulfenamido) pyrimidine was extracted with hot acetone. The acetone was concentrated somewhat and the product was precipit/ated with water andoxidized.

25 parts of 2- (m-nitrobenzenesulfenamido') pya rimidine were'suspended in 400 cc. of acetone and added to 500 cc. of 6% aqueous potassium permanganate containing 10 cc. of 10% sodiumhydroxide. When the reactionwas over, the suspension was filtered and the 2-(m-nitrobenzenesulfonamido) pyrimidine was precipitated from the filtrate by acidification.

This example illustrates another method of preparing the compounds of the preesnt invention. In this process an aminodiazine is reacted with a meta substituted benzenesulfenyl halide to form a benzenesulienamido diazine which is then oxidized to the desired sulfonamidodiazine.v

EXAMPLE 39 2- (m-nitrobenzenesulfonamido) --chlorop:zj-v rimidine 28 parts of m-nitrobenzenesulfonyl bromide (Beilstein, XI, 70-) and 12. parts'of 2-amino-5-e chloropyrimidine (prepared by the chlorination of aminopyrim'idine in acid solution) were mixed with'lO parts of pyridine and refluxed for .two hours. This solutionwas poured into 400 parts of water containing 75 parts of hydrochloric acid. The separated solid was filtered. The 2-(m-ni trobenzenesulfonamido) -5-chloropyrimidine was purified by solution in alkali, filtration, and reprecipitation with acid after treatment with charcoal. The product melted at 234-237 C.

This process utilizes a sulfonyl bromide in place of a sulfonyl chloride as shown in previous, examples.

EXAMPLE 40 2- (m-nitrobeneenesulfonamido) pyrimidine 28 parts of m-nitrobenzenesulfonyl bromide and 14 parts of Z-aminopyrimidine were mixed with 25 parts of anhydrous pyridine and the reaction mixture was heated for minutes on the steam bath, and after 30 minutes standing was poured into 700 parts of water. The 2-(m-nitrobenzenesulfonamido) pyrimidine was filtered off and dried. The product may be purified by solution in alkali, treatment with charcoal, filtration, and reprecipitation with acid. 19 parts melting at 21'7"-219 C. were obtained-.-

T4 EXAMPLEII 2-metanilamido-5-eIiZo1-opyrimid'ine 60 parts of metanilamide were added to parts of nitrobenzene and the mixture was heated;

to 140 C. To the resultingsolution were added 40 parts of potassium carbonate and 60 parts of 2,5-dichloropyrimidine .withvigorous stirring. The temperature was increased to 190 C. slowly and then lowered-to, and maintained at, C. for four hours. The nitrobenzene was steam distilled and the pH- of .the aqueousresidue was adjusted to 8. After filtration, the solution was treated with charcoal, filtered, and the 2-iri'etanilam'ido-5-chloropyrimidine' was precipitated by acidification. This material could be further purified through its hydrochloride as described in Example 32. 53 parts, melting at 228230 d;

were obtained. The direct reaction of meta'nil amide with a dichlordia'aine is illustrated in the above example;

EXAMPLE 42 Z-metariilamido-4,6-dimethylpyrimidi1ie 107 parts of metanilylguanidine and 51 parts of acetylacetone were mixed and heated iiran oil bath at 130 C. for 24 hours. The reaction mixture was cooled and the 2"-metanilamido-4,6- dimethylpyrimidine was extracted with alkali. After filtration and treatment with charcoal it was precipitated by acidification. The melting point was 225-226.5 C. This example illustrates an unusual method of preparing compounds of the present invention by cyclization of the guanidine group by means of acetylacetone.

EXAMPLE 43 2- (m-nitiobenzenesulfonamido) -5-bromopyrimidine A boiling solution of 32 parts of Z-Km-nitrobenzenes'ulfonamido) pyrimidine in 500 parts of acetic acid was treated with 27 parts of bromine in 250 parts of acetic acid. The solution was refluxed .for 20 minutes, chilled, and the separated crystals filtered. The melting point of the product thus obtained was not depressed when mixed with a sample of 2-(m-nitrobenZehesulfohamido)' 5-'bromopyrimidine, prepared as described in Example 48.

The direct bromination of-the diazine group in ameta-s'ubstituted benzene sulfonamidodiazirie is shown above-.- v

EXAMPLE 4'4 2-metanilamidopyr ifiiidiize A solution of 34 partsof 2-benezenesulfonamidopyrimidine in a mixture of 100 parts of nitric acid (d:1.42) and ,50 parts of 20% oleum was heated for 30 minutes at 40-80 C. The product was poured into 1000 parts 0f .water and made just alkaline with ammonium hydroxide and then acid with aceticacid: The solidwhich separated was filtered and dried.

'75 parts of the materialthus obtained: Were dissolved in a mixture of 200 parts of: ammonium hydroxide (d:0.9) and 200 parts of water andthe solutionsaturated with hydrogen sulfide gas: Themixture thus obtained was boiled for 10 minutes, made' strongly acid with hydrochloric acid, treated with charcoal, and filtered. The filtrate was made alkaline with ammonium hydroxide and then acid with acetic-acid- The-solidwhich separatedwas filtered and dried-L Its meltingpoint was notdepressed by 2'-metanilamidopy-; rimidine, prepared as described in Example 2;

The nitration of a benzenesulfonainidodiazine to obtain a meta-nitrobenzenesulfonamidodiazine and subsequent reduction of the nitro group as a distinct method of preparing our new compounds is illustrated. in this example.

EXAMPLE 45 N -methyZ-2-metaniiamido-5-chloropyrimidine HgN N EXAMPLE 46 Z-metanilamidopyrimidine 10 parts of 2-aminopyrimidine and 10 parts of m-aminobenzenesulfonyl fluoride were mixed and heated for several hours at 150-l80 C. When the mixture was nearly solid it was cooled and boiled with 300-500 cc. of water and filtered. Upon cooling the filtrate, the crude 2-metanilamidopyrimidine separated and was purified by treatment of its alkaline solution with charcoal.

The use of sulfonyl fluorides in the direct coupling of a meta-aminobenzene sulfonyl group with a 2-aminodiazine is illustrated above.

EXAMPLE 47 2- (3-nitrobenzenesulfonamido) --chlor0- pyrimidine 40 parts of m-nitrobenzenesulfonyl fluoride and 24 parts of 2-amino-5-chloropyrimidine were mixed with 150 parts of pyridine and refluxed for 4 hours. The solution was poured into 1000 parts of water and the separated 2-(3-nitrobenzenesulfonamido) 5 chloropyrimidine was filtered off and purified by treatment of its alkaline solution with charcoal.

EXAMPLE 48 2- (3-nitrobenzenesulfonamido) -5-bromopyrimidine 50 parts of 2-amino-5-bromopyrimidine and '70 parts of m-nitrobenzenesulfonyl chloride were added to 210 parts of pyridine and the whole Was refluxed for two hours. The reaction mixture was poured into 1000 parts of 1:4 hydrochloric acid and the 2-(3-nitrobenzenesulfonamido) -5-bromopyrimidine was filtered off. It was purified by treatment of its alkaline solution with charcoal. 50 parts, melting point 243-245 C., were obtained. It could also be crystallized from acetic acid which raised the melting point to 245-247 C.

16 EXAMPLE 49 2-metanilamido-5-bromopyrimidin 46 parts of 2-(3-nitrobenzenesulfonamido)-5- bromopyrimidine were added to 200 parts of 1:1 ammonia and the mixture was saturated with hydrogen sulfide gas. The mixture was then boiled, cooled, and made acid. The solid was filtered and dissolved in alkali. This solution was clarified with charcoal and the 2-metanilamido-5-brcmopyrimidine was collected. It was purified by crystallization of its hydrochloride from dilute (1:20) hydrochloric acid and conversion of the salt to the free compound. 26 parts were obtained, the melting point being 238.5-240 C.

EXAMPLE 50 2-benzenesulfonamido-5-bromopyrimidine A solution of 1.7 parts of Z-benzenesulfonamidopyrimidine (English, Chappell, Bell and Roblin, J. Am. Chem. Soc. 64, 2516 (1942)) in 50 parts of boiling acetic acid was treated with a solution of 3.2 parts of bromine in 25 parts of acetic acid. The mixture was refluxed for 2 hours, cooled, and the separated solid filtered. This product was dissolved in dilute ammonium hydroxide solution, treated with charcoal, and reprecipitated with acetic acid. The melting point was 239-241 C.

EXAMPLE 51 2-metanilamido-5-bromopyrimidine A solution of 16 parts of Z-benzenesulfonamido- 5-bromopyrimidine (Example 50) in a mixture of 33 parts of 20% oleum and 6'7 parts of ordinary nitric acid (d:l.42) was heated for an hour at 50-'75 C. and then poured into 1000 parts of water. The solid which separated was filtered and dissolved in 250 parts of ammonium sulfide solution. The resulting solution was boiled until a precipitate was obtained. The mixture was then made strongly acid with hydrochloric acid and filtered hot. The filtrate was made alkaline with ammonium hydroxide, treated with charcoal, filtered, and the filtrate made acid with acetic acid. The solid which separated was filtered' and dried. Its melting point was not depressed when mixed with an authentic sample of 2-metanilamido-5-bromopyrimidine (Example 49).

This example, with Example 50, shows the direct bromination of the diazine group of a 2-benzenesulfonamidodiazine, th subsequent nitration of the benzene ring and the reduction of the meta-nitro radical to a meta-amino radical.

EXAMPLE 52 2,5 -dz'chl0ropyrimidine 128 parts of 2-hydroxy-5-chloropyrimidine were mixed with 500 parts of POC13 and refluxed one hour. 400 parts of POCla were distilled and the residue was worked up with ice and water. The aqueous mixture was neutralized with about 300 parts of sodium carbonate. The resulting 2,5- dichloropyrimidine may be steam distilled directly from the neutralized mixture or may be extracted with a sol-vent. It may be distilled or crystallized EXAMPLE SB" 2 hydmw-5-chloropyrimidine 20 parts or 2-amino-5-chloropyrimidine were added slowly to a hot mixture of 20 parts of concentrated sulfuric acid and 80 parts of water. The mixture was cooled to C. with stirring. The sulfate of the amine separated as a magma of small crystals. With stirring, keeping the temperature below 10 C., 10.7 parts of sodium nitrite dissolved in 30 parts of water were added in the course of ninety minutes. The mixture was stirred for an additional hour and left at room tempera ture overnight. The mixture was then warmed on a steam bath and 70 parts of concentrated ammonium hydroxide gradually added. On cooling the ammonium salt of 2-hydroxy-5-chloropyrimidine crystallized out. It was filtered and dissolved in 80 parts of hot water. On acidification of the hot solution with 11 parts of glacial acetic acid the desired product was precipitated. After filtering and washing with water, 12.8 parts of 2 hydroxy--chloropyrimidine were obtained. Melting point was 237-238 C. with decomposition. The decomposition point is variable depending on the rate of heating.

EXAMPLE 54 m-Nit1"0benzenesulfonylguanidine OaN NH 120 parts of guanidine nitrate were suspended in 700 parts of acetone and treated with 150 parts of N sodium hydroxide. The mixture was stirred and cooled to 10 C. and treated with 111 parts of m-nitrobenzenesulfonyl chloride in three portions. When the reaction was over, 1000 parts of water were added and the precipitated crude m-nitrobenzenesulfonylguanidine was filtered off. It was purified by leaching with dilute alkali and crystallization from aqueous isopropanol (1:1). Melting point was 198-200 C.

EXAMPLE 55 M etanilylgucmidine HQN NH 33 parts of m-nitrobenzenesulfonylguanidine from Example 54 were suspended in 2000 parts of alcohol and reduced with hydrogen at 50 pounds pressure in the presence of Raney nickel catalyst. The solution was warmed and filtered from the catalyst. The filtrate was cooled to give metanilylguanidine. Further crops could be collected by concentration of the filtrate. The melting point, after treatment with charcoal in acid solution, was 185.5-189 C.

EXAMPLE 56 2- (m-nitrobenzenesulfonamido) -5-br0mo- 4-methylpyrimidine 94 parts of 2-amino-5-bromo-4-methylpyrimidine were suspendedin partsofpyridine with 150 parts of m-nitrobenzenesulfonyl chloride. The mixture was left for sixteen hours at 40- C. and. then pour-ed into water. The dark. precipitate of 2 (m-nitrob'enzenesulfonamido) 5 bromo 4 methylpyrimidine was collected and purified by treatment in alkaline solution with charcoaland' by crystallization i'rom -a'cetic acid.

EXAMPLE 5"? Z-metdnildrfzidd- 5 bibifiO-Qmthylpyrimidifie 50 parts of 2-(m-nitro-benzenesulfonamido) -5- bromo-4-methylpyrimidine were suspended in 450 parts of 1:1 ammonia and the mixture was saturated with hydrogen sulfide. The resulting mixture was boiled to half volume and acidified with acetic acid. The precipitated crude 2-metanilamido-5-bromo-4=-methylpyrin1idine was collected. and purified by treatment of its alkaline solution with charcoal and by crystallization of its hydrochloride, as described for Z-metanilamido-E-bromopyrimidine in Example 51, or for Z-metanilamido-fi-chloropyrimidine in Example 32.

What we claim is:

1. A method of preparing Z-meta-aminobenzenesulfonamido-S-halopyrimidines which comprises mixing together and reacting a meta-nitrobenzenesulfonyl halide with Z-aminopyrimidine in the presence of a tertiary amine, treating the reaction product with a halogen, and thereafter reducing the meta-nitro group to an aminogroup.

2. A method of preparing Z-meta-aminobenzenesulfonamido-5-bromopyrimidine which comprises mixing together and reacting a meta-nitrobenzenesulfonyl halide with Z-aminopyrimidine in the presence of a tertiary amine, treating the reaction product with bromine, and thereafter reducing the meta-nitro group to an amino group.

3. A method of preparing 2-meta-aminobenzenesulfonamido-5-chloropyrimidine which comprises mixing together and reacting a meta-nitrobenzenesulfonyl halide with Z-aminopyrimidine in the presence of a tertiary amine, treating the reaction product with chlorine, and thereafter regroup.

5. 2 (meta aminobenzenesulfonamido) 5- halopyrimidine.

6. 2 (meta aminobenzenesulfonamido) 5- chloropyrimidine.

7. 2 (meta aminobenzenesulfonamido) 5- bromopyrimidine.

JACKSON 1?. ENGLISH. JOE H. CLARK.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,898,431 Dressel et al Feb. 21, 1933 2,299,555 Mietzsch et a1 Oct. 20, 1942 (Other references on following page) 19 20 UNITED STATES PATENTS Number Country Date 116 165 Australia Aug. 18 1941 Number Name Date 21324013 Moore at all July 13, 1943 317,338 Great Brltam Aug. 13, 1929 2,407,966 Sprague Sept. 17, 194 6 OTHER REFERENCES 2,410,793 Winnek et a1 Nov. 5, 1946 0 2,423,108 Moore July 1, 1947 331 55 Amer Chem August 1940 paes FOREIGN PATENTS Cogshill, Jour. Am. Med. Assn. 117, 1077-4081 (1941) Number Country Date 4, 1 Australia May 2 10 n p 

1. A METHOD OF PREPARING 2-META-AMINOBENZENSULFONAMIDO-5-HALOPYRIMIDINES WHICH COMPRISES MIXING TOGETHER AND REACTING A META-NITROBENZENESULFONYL HALIDE WITH 2-AMINOPYRIMIDINE IN THE PRESENCE OF A TERTIARY AMINE, TREATING THE REACTION PRODUCT WITH A HALOGEN, AND THEREAFTER REDUCING THE META-NITRO GROUP IN AN AMINOGROUP.
 5. 2-(META-AMIHOBENZENESULFONAMIDO)-5-HALOPYRIMIDINE. 